Posttraumatic stress disorder (PTSD) is extremely common among Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) Veterans, impacting approximately 20% of OEF/OIF/OND Veterans enrolled in VA healthcare. Pharmacological management of PTSD is unfortunately frequently suboptimal, and many OEF/OIF/OND Veterans experience persistent and unalleviated symptoms. Currently there are only two FDA-approved pharmacological treatments for PTSD (sertraline and paroxetine, each approved ~15 years ago). There is thus an acute and urgent need for the development of new pharmacological treatments for PTSD that are effective and well-tolerated. Neurosteroids are endogenous molecules that are enriched in human brain, and many neurosteroids exhibit anxiolytic-like actions and modulate the HPA axis. In addition, neurosteroids such as dehydroepiandrosterone (DHEA) are immediately accessible for translation to clinical trials, as DHEA is available over-the-counter as a dietary supplements in the U.S. Neurosteroid interventions may represent an important new lead for the management of PTSD symptoms in OEF/OIF/OND Veterans. Based on our preliminary data in 660 OEF/OIF/OND male Veterans (indicating DHEAS levels as significantly reduced in PTSD) and rodent data from multiple research groups demonstrating anxiolytic actions of neurosteroids, we proposed the following: A parallel-group, double-blind, placebo (PBO)-controlled, randomized Phase 2 pilot study using adjunctive DHEA (400 mg) will be evaluated to establish Proof of Concept (POC) for this agent in Veterans with PTSD. Our first objective is POC target engagement to evaluate a one-time adjunctive oral dose of DHEA (400 mg) relative to PBO on the neuronal circuity of fear-anxiety-emotion connectivity. This will be achieved by comparing pre- to post-treatment changes in amygdala-hippocampal functional connectivity to DHEA and PBO during fMRI activation. We hypothesize that compared with PBO, DHEA will increase task-associated fMRI functional connectivity between the amygdala and hippocampus (primary outcome). Our second objective is to determine if a 6-week treatment with adjunctive DHEA is superior to PBO in reducing symptoms of PTSD (CAPS-5) and depression (BDI) in OEF/OIF/OND Veterans, and enhancing resilience (CD-RISC). We hypothesize that 400mg DHEA will result in reduced PTSD and depression symptom severity relative to PBO, as determined by a pre- to post-treatment decrease in CAPS-5 and BDI scores, respectively, with enhancement in resilience scores using the CD-RISC at 6-weeks. Our third objective is to evaluate the impact of DHEA relative to PBO on serum neurosteroid levels in OEF/OIF/OND Veterans with PTSD. We hypothesize that DHEA will result in a statistically-significant increase in serum neurosteroid levels (DHEA, DHEAS, androsterone) relative to PBO, as determined by pre- to post-treatment reductions in PTSD symptoms severity. This association will be evaluated by correlating neurosteroid levels with PTSD, depression, and resilience scores over 6 weeks of treatment. Our exploratory objective is to determine preliminary evidence for an association of fMRI and myelin integrity measures of fear-anxiety-emotion circuits with serum neurosteroid levels and treatment response to DHEA. Changes in myelin integrity following DHEA treatment will be evaluated using novel susceptibility diffusion imaging [STI]), as DHEA impacts myelination in preclinical rodent models. We will also determine if serum neurosteroid levels are correlated with myelin integrity on STI. We hypothesize that fMRI and myelin integrity of fear-anxiety circuits will correlate with serum neurosteroids and treatment response. Significance: This project may lead to a novel new therapeutic for OEF/OIF/OND Veterans with PTSD that is safe, efficacious, inexpensive, and well-tolerated. It could also identify serological and/or neuroimaging biomarkers for therapeutic response, potentially leading to personalized treatments for Veterans with PTSD